The cell cycle is tightly regulated to ensure proper cell division and growth. Cyclin-dependent kinases (CDKs) play a crucial role in controlling cell cycle progression. In particular, CDK4 and CDK6 partner with D-type cyclins during the G1 phase to phosphorylate and inactivate the retinoblastoma (Rb) tumor suppressor protein. This allows the release of E2F transcription factors that trigger the expression of genes required for the G1 to S phase transition and cell division.

Credit to Reactome: Cell Cycle

In many cancers, the CDK4/6-cyclin D-Rb pathway is dysregulated, leading to excessive proliferation. Frequent alterations include overexpression of D-type cyclins, loss of CDK inhibitors, and Rb mutations/deletions. Consequently, CDK4/6 represent attractive anti-cancer targets.

Ammazzalorso, A., Agamennone, M., De Filippis, B. & Fantacuzzi, M. Development of CDK4/6 Inhibitors: A Five Years Update. Molecules 26, 1488 (2021).

Current Drug Approvals and Development

Early CDK inhibitors like flavopiridol lacked selectivity and caused high toxicity. However, intensive efforts to develop selective CDK4/6 inhibitors led to the FDA approval of Palbociclib (Ibrance), Ribociclib (Kisqali) and Abemaciclib (Verzenio) for HR+/HER2- metastatic breast cancer. These orally bioavailable small molecule drugs compete with ATP in the kinase domain of CDK4/6. They induce G1 arrest in cancer cells by blocking Rb phosphorylation. In addition to three CDK4/6 inhibitors approved for treatment of breast cancer, another CDK4/6 inhibitor, Trilaciclib (Cosela) was approved as a first-in-class for myeloprotection.

Challenges in Optimizing CDK4/6 Inhibition

Despite the significant progress in CDK4/6 inhibition, various challenges remain in optimizing these targeted therapies:

• The high homology between CDK family members makes selectivity difficult. Inhibiting other CDKs like CDK1 and CDK2 causes toxicity.

• Tumors develop resistance through RB loss, cyclin E/CDK2 upregulation, and bypass signaling pathways. Combinations are being tested to overcome these.

• CDK4/6 inhibitors often induce senescence in solid tumors while hematologic malignancies undergo apoptosis. The optimal response differs by cancer type.

• Robust biomarkers to predict sensitivity across diverse tumors are still lacking.

• Certain on-target effects like myelosuppression have been observed. Structural modifications and dosing optimizations are being pursued to improve toxicity profiles.

• Issues like poor solubility, fast metabolism/excretion, and drug-drug interactions need to be addressed.

• Differences in CDK4/6 dependency and compensatory mechanisms contribute to variable clinical responses.

Exploring Additional Strategies for CDK4/6 Inhibition

Researchers are pursuing innovative strategies to further optimize CDK4/6 inhibition and expand their clinical utility:

• Developing compounds that also inhibit CDK2 may improve efficacy and overcome resistance mediated by CDK2 compensation.

• PROTAC degraders that harness the ubiquitin-proteasome system to induce degradation of CDK4/6 proteins could provide more durable target inhibition.

• Combination therapies, such as with endocrine therapy in breast cancer or immunotherapy in other cancers, leverage synergistic effects on cancer cell proliferation and immune function.

• Alternate schedules (e.g. CDK4/6 inhibitor after chemotherapy) are being tested to enhance cytotoxicity.

• Potential applications in cancer prevention and as supportive care to reduce toxicity of chemotherapy and radiation are also being evaluated.

Overall, CDK4/6 remain among the most promising cell cycle targets in cancer drug discovery. Rational drug design has enabled the development of selective inhibitors. However, a nuanced understanding of normal versus pathogenic CDK4/6 signaling is vital to address current challenges and expand the clinical utility of these targeted therapies.

References

Ammazzalorso, A., Agamennone, M., De Filippis, B. & Fantacuzzi, M. Development of CDK4/6 Inhibitors: A Five Years Update. Molecules 26, 1488 (2021).

Chen, P., Xu, Y., Li, X., Yao, H. & Lin, K. Development and strategies of CDK4/6 inhibitors. Future Medicinal Chemistry 12, 127–145 (2020).

Fassl, A., Geng, Y. & Sicinski, P. CDK4 and CDK6 kinases: From basic science to cancer therapy. Science 375, eabc1495 (2022).

Goel, S., Bergholz, J. S. & Zhao, J. J. Targeting CDK4 and CDK6 in cancer. Nat Rev Cancer 22, 356–372 (2022).